Ian W. Flinn, MD, PhD: Josh, one of the most exciting things that’s happening throughout oncology is the immunotherapies. That’s your particular specialty. What excites you in immunotherapy for follicular lymphoma?

Joshua Brody, MD: Ian, as you know, I’m easily excitable. The answer is everything.We know—it’s not an opinion, it’s a fact—that T cells can kill cancer, but they can kill low-grade lymphoma specifically. You can see this very easily in the small but impressive CAR T-cell trials for follicular lymphoma. So, if you can get a T cell sufficiently excited, clearly they can kill higher-grade but also low-grade lymphomas thoroughly and give durable responses. We’ve seen these in small data sets. So, it’s about how can we get those T cells to hate those cancer cells in the first place. I will say that, as opposed to the anti–PD-1 revolution in much of oncology, PD-1 monotherapy has been underwhelming in follicular lymphoma, the other low-grade lymphomas. We have a few patients who have long-term remissions. Probably everyone has, from some trials, people in remission for a few years. But the response rates are low, so how can we improve those?

Ian W. Flinn, MD, PhD: Well, why is it low to begin with?

Joshua Brody, MD: I’ll tell you why it’s not low: because we have predictors for PD-1 response in other cancers. Some of those predictors are tumor mutation burden. If there are not enough neoantigens to recognize, they won’t be able to attack the tumor. Neoantigen burden or mutational burden is a good predictor in other tumors. So, it’s not low because follicular lymphoma lacks neoantigen or tumor mutation burden. It is comparable to some of the other responsive tumors and, similarly, some of the other predictors for PD-1 responsiveness: CD8 T-cell infiltration into the tumor, PD-L1 expression by the tumor, interferon-gamma signature within the tumor. Follicular lymphoma has all of those things, so it should be responding. So, why isn’t it responding? Some difference in perhaps the T-cell activation state. That’s kind of a vague term.

There’s one other great correlate that’s been seen in other tumors for who will respond to PD-1 blockade. This is some work by University of Chicago—Thomas Gajewski and Stefani Spranger—that showed it’s not just about the tumor having antigens, it’s about the tumor having antigen-presenting cells, dendritic cells specifically. We call this Batf3 subset of dendritic cells. In multiple other tumor types, Batf3 dendritic cell transcriptomics in the tumor were a great predictor of responsiveness to PD-1 blockade. So maybe, just by increasing dendritic cell infiltration to those tumors, we can get those checkpoint blockade therapies to be highly effective. Lots of ongoing trials of approaches like that: intratumoral STING agonists, intratumoral TLR agonists, into the tumors combined with PD-1 blockade—early promising data about that.

Then the other approach, is just to combine with something that we know will get some effector cells into the tumor; the obvious thing being rituximab, which will bring NK cells and perhaps other inflammatory things into the tumor as well. We sometimes say that the field of immunotherapy is PD-1 plus X equals dollars. That’s a bit mundane, I apologize, but solve for X. So, X could be rituximab, X could be some of these other things. We have ways of improving the efficacy of PD-1 blockade or checkpoint blockade, generally, and probably not increasing toxicity very much. We have some early data at ASCO, for example, about the rituximab plus PD-1 blockade, rituximab plus pembrolizumab. We have this early study of Gazyva (obinutuzumab); obinutuzumab plus bendamustine plus atezolizumab PD-L1 blockade, both with pretty promising early data.

Ian W. Flinn, MD, PhD: I always think of chemotherapy as being immunosuppressive. So, is that a concern?

Joshua Brody, MD: I think it absolutely is, and chemotherapy can be immunosuppressive. But all chemotherapies are not born equally with this.

Ian W. Flinn, MD, PhD: But bendamustine kills T cells.

Joshua Brody, MD: Absolutely. Bendamustine is not any immune cell’s friend really, but some other chemotherapies actually could be. People have taken a very open-minded approach to this in the lab, using large panels of different chemotherapies; some of these were the best studies, before bendamustine was widely used. One of these studies compared many chemotherapies to test, not on the T cells or the immune cell side, but on the tumor cell side, which induced immunogenic cell death. At the top of the list was anthracyclines, which was news to me. I never knew that before that study. They actually had a correlate for which the immunogenic cell death chemotherapies can be read out by those that induced more calreticulin on the T cells.

We don’t have to do this big study again. We can, even in the test tube, test novel chemotherapies for their induction of calreticulin on tumor cells. This is across a few different tumor types. It was true in melanoma, colon cancer, and some lymphoid malignancies as well. So, some chemotherapies could combine well. I agree with you that bendamustine is concerning, and it is amazing or interesting, provocative let’s say, that just the rituximab plus PD-1 early data look to be comparable—not as a head-to-head study, of course, as the obinutuzumab plus bendamustine plus atezolizumab data.

Ian W. Flinn, MD, PhD: Matt, what about CAR T cells? Josh just gave this eloquent need for engaging the T cells. CAR T cells are an obvious choice. It’s working in large cell lymphoma.

Matthew Lunning, DO: Yes, CD19 still sits on the follicular lymphoma cell. So, I think it’s going to come down to the risk-benefit. Can we find the right population of follicular lymphoma patients who deserve a try for CAR T cells? We talked about the early relapsing population. If they continue to go down that track, that might be the place to go after, or people who are having short remission durations. But I think we’re sorting out the toxicities. We’re getting better at doing CAR T cells. We’re getting into the frame, where you can have, in 1 hospital, 3 constructs, whether or not it’s 2 approved and 1 on clinical trial. That can now happen, so we’re getting there, and I think it’s just a matter of time. It’s already in clinical trials. It’s just a matter of time until we are able to have those discussions also with the patients with relapsed/refractory follicular lymphoma.

Joshua Brody, MD:I agree with Matt, that finding the right patient for the current risk-benefit ratio of CAR T cells is important. But then, also the generation 3.0 CAR T cells will have a different risk-benefit ratio for everyone. They will be safer; lots of examples of that. But one of them is not very far along yet; the suicide switch, modulator switch CAR T cells, like the inducible Cas9 or other similar technologies where we can turn off the CAR T cell, either when it becomes toxic or even before it becomes toxic. Once we make safe CAR T cells, it will be easier logistically, maybe not financially, to get them in for patients with low-grade lymphomas.

Transcript Edited for Clarity

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Transcript:

Ian W. Flinn, MD, PhD: Josh, one of the most exciting things that’s happening throughout oncology is the immunotherapies. That’s your particular specialty. What excites you in immunotherapy for follicular lymphoma?

Joshua Brody, MD: Ian, as you know, I’m easily excitable. The answer is everything.We know—it’s not an opinion, it’s a fact—that T cells can kill cancer, but they can kill low-grade lymphoma specifically. You can see this very easily in the small but impressive CAR T-cell trials for follicular lymphoma. So, if you can get a T cell sufficiently excited, clearly they can kill higher-grade but also low-grade lymphomas thoroughly and give durable responses. We’ve seen these in small data sets. So, it’s about how can we get those T cells to hate those cancer cells in the first place. I will say that, as opposed to the anti–PD-1 revolution in much of oncology, PD-1 monotherapy has been underwhelming in follicular lymphoma, the other low-grade lymphomas. We have a few patients who have long-term remissions. Probably everyone has, from some trials, people in remission for a few years. But the response rates are low, so how can we improve those?

Ian W. Flinn, MD, PhD: Well, why is it low to begin with?

Joshua Brody, MD: I’ll tell you why it’s not low: because we have predictors for PD-1 response in other cancers. Some of those predictors are tumor mutation burden. If there are not enough neoantigens to recognize, they won’t be able to attack the tumor. Neoantigen burden or mutational burden is a good predictor in other tumors. So, it’s not low because follicular lymphoma lacks neoantigen or tumor mutation burden. It is comparable to some of the other responsive tumors and, similarly, some of the other predictors for PD-1 responsiveness: CD8 T-cell infiltration into the tumor, PD-L1 expression by the tumor, interferon-gamma signature within the tumor. Follicular lymphoma has all of those things, so it should be responding. So, why isn’t it responding? Some difference in perhaps the T-cell activation state. That’s kind of a vague term.

There’s one other great correlate that’s been seen in other tumors for who will respond to PD-1 blockade. This is some work by University of Chicago—Thomas Gajewski and Stefani Spranger—that showed it’s not just about the tumor having antigens, it’s about the tumor having antigen-presenting cells, dendritic cells specifically. We call this Batf3 subset of dendritic cells. In multiple other tumor types, Batf3 dendritic cell transcriptomics in the tumor were a great predictor of responsiveness to PD-1 blockade. So maybe, just by increasing dendritic cell infiltration to those tumors, we can get those checkpoint blockade therapies to be highly effective. Lots of ongoing trials of approaches like that: intratumoral STING agonists, intratumoral TLR agonists, into the tumors combined with PD-1 blockade—early promising data about that.

Then the other approach, is just to combine with something that we know will get some effector cells into the tumor; the obvious thing being rituximab, which will bring NK cells and perhaps other inflammatory things into the tumor as well. We sometimes say that the field of immunotherapy is PD-1 plus X equals dollars. That’s a bit mundane, I apologize, but solve for X. So, X could be rituximab, X could be some of these other things. We have ways of improving the efficacy of PD-1 blockade or checkpoint blockade, generally, and probably not increasing toxicity very much. We have some early data at ASCO, for example, about the rituximab plus PD-1 blockade, rituximab plus pembrolizumab. We have this early study of Gazyva (obinutuzumab); obinutuzumab plus bendamustine plus atezolizumab PD-L1 blockade, both with pretty promising early data.

Ian W. Flinn, MD, PhD: I always think of chemotherapy as being immunosuppressive. So, is that a concern?

Joshua Brody, MD: I think it absolutely is, and chemotherapy can be immunosuppressive. But all chemotherapies are not born equally with this.

Ian W. Flinn, MD, PhD: But bendamustine kills T cells.

Joshua Brody, MD: Absolutely. Bendamustine is not any immune cell’s friend really, but some other chemotherapies actually could be. People have taken a very open-minded approach to this in the lab, using large panels of different chemotherapies; some of these were the best studies, before bendamustine was widely used. One of these studies compared many chemotherapies to test, not on the T cells or the immune cell side, but on the tumor cell side, which induced immunogenic cell death. At the top of the list was anthracyclines, which was news to me. I never knew that before that study. They actually had a correlate for which the immunogenic cell death chemotherapies can be read out by those that induced more calreticulin on the T cells.

We don’t have to do this big study again. We can, even in the test tube, test novel chemotherapies for their induction of calreticulin on tumor cells. This is across a few different tumor types. It was true in melanoma, colon cancer, and some lymphoid malignancies as well. So, some chemotherapies could combine well. I agree with you that bendamustine is concerning, and it is amazing or interesting, provocative let’s say, that just the rituximab plus PD-1 early data look to be comparable—not as a head-to-head study, of course, as the obinutuzumab plus bendamustine plus atezolizumab data.

Ian W. Flinn, MD, PhD: Matt, what about CAR T cells? Josh just gave this eloquent need for engaging the T cells. CAR T cells are an obvious choice. It’s working in large cell lymphoma.

Matthew Lunning, DO: Yes, CD19 still sits on the follicular lymphoma cell. So, I think it’s going to come down to the risk-benefit. Can we find the right population of follicular lymphoma patients who deserve a try for CAR T cells? We talked about the early relapsing population. If they continue to go down that track, that might be the place to go after, or people who are having short remission durations. But I think we’re sorting out the toxicities. We’re getting better at doing CAR T cells. We’re getting into the frame, where you can have, in 1 hospital, 3 constructs, whether or not it’s 2 approved and 1 on clinical trial. That can now happen, so we’re getting there, and I think it’s just a matter of time. It’s already in clinical trials. It’s just a matter of time until we are able to have those discussions also with the patients with relapsed/refractory follicular lymphoma.

Joshua Brody, MD:I agree with Matt, that finding the right patient for the current risk-benefit ratio of CAR T cells is important. But then, also the generation 3.0 CAR T cells will have a different risk-benefit ratio for everyone. They will be safer; lots of examples of that. But one of them is not very far along yet; the suicide switch, modulator switch CAR T cells, like the inducible Cas9 or other similar technologies where we can turn off the CAR T cell, either when it becomes toxic or even before it becomes toxic. Once we make safe CAR T cells, it will be easier logistically, maybe not financially, to get them in for patients with low-grade lymphomas.